1-disubstituted aminopyrazoles

ABSTRACT

1-(Disubstituted-amino)pyrazole compounds are provided herein of the formula: WHEREIN EACH OF R1 and R2 stands for lower alkyl or R1 and R2, taken together with the adjacent N-atom form morpholino, piperidino, pyrrolidino, N-methylpiperazino, N-benzylpiperazino and N-phenylpiperazino, R&#39;&#39;s, which are the same or different from each other, stand for hydrogen, alkyl having one to ten carbon atoms, phenyl, naphthyl, phenyl or naphthyl substituted by halogen or lower alkyl, respectively, and R3 stands for hydrogen, lower alkyl, N,N-di-loweralkylaminoethyl, N-morpholinomethyl, Npiperidinomethyl, N-pyrrolidinomethyl, N-methylpiperazinomethyl, N-benzylpiperazinomethyl and N-phenylpiperazinomethyl. The above compounds as well as the pharmaceutically acceptable salts thereof are useful as analgesics, antipyretics and mild muscle relaxants.

llnite States Patent Noguchi et al.

[ l-DISUBSTITUTED AMINOPYRAZOLES [72] Inventors: Shunsaku Noguchi; ShojiKishimoto, both of Osaka; Kiyohisa Kawai, Kyoto, all of Japan [73]Assignee: Takeda Chemical Industries, Ltd.,

l-ligashi-ku, Osaka, Japan [22] Filed: May 8, 1970 [21] Appl. No.:35,926

[52] US. Cl. ....260/3l0 R, 260/247.5 R, 260/268 N, 260/268 H,260/293.63, 260/293.67,

[5 l] Int. Cl. ..C07d 49/20 [58] Field of Search ..260/310 R, 247.5 R,268 N, 260/268 H, 293.7, 293.63

[56] References Cited UNlTED sTATEs PATENTS 3,254,093 5/1966 l-luijgenet al ..260/3 10 R 3,207,763 9/1965 Harder ..2 o/31o R 3,274,203 9/1966Dickinson ..260/310 R 3,312,690 4/1967 Masuda et al. ..260/307 F FOREIGNPATENTS 0R APPLICATIONS 44/32,411 12/1969 Japan ..260/307 F OTHERPUBLICATIONS Imashiro et al., Chem. Abst., Vol. 72, No. 1ll482q (1970).

1 1 Sept. 26, 1972 Primary Examiner-Natalie Trousof Attorney-Wenderoth,Lind & Ponack [57] 7 ABSTRACT l-(Disubstituted-amino)pyrazole compoundsare provided herein of the formula:

wherein each of R and R stands for lower alkyl or R and R taken togetherwith the adjacent N-atom form morpholino, piperidino, pyrrolidino,N-methylpiperazino, N-benzylpiperazino and N-phenylpiperazino, Rs, whichare the same or different from I each other, stand for hydrogen, alkylhaving one to 10 Claims, No Drawings l-DISUBSTITUTED AMINOPYRAZOLES Thisinvention relates to a novel and useful l-(disubstituted-amino)pyrazoleand to the production of it. More concretely, this invention relates toa novel amino pyrazole of the general formula (I) and acid salts thereofwhich have characteristic effects as analgesics, antipyretics and mildmuscle relaxants, etc.

wherein each of R and R stands for a lower alkyl or R and R takentogether with the adjacent N-atom, form a heterocyclic ring, Rs, whichare the same with or different from each other, stand for hydrogen,alkyl, aryl or substituted aryl respectively, R stands for hydrogen,lower alkyl or N,N-disubstituted aminomethyl.

The lower alkyl represented by each of R, R and R in the formula (I) isexemplified by alkyl having from one to five carbon atoms such asmethyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert.-butyl, amyl, isoamyl, etc., when R and R taken together with theadjacent nitrogen atom form a heterocyclic ring, the ring isexemplified'by a five or six membered heterocyclic ring such asmorpholino, piperidino, pyrrolidino, N-substituted piperazino, forexample, N- methylpiperazino, N-benzylpiperazino, N-phenylp1peraz1no,etc.

The alkyl represented by R may be straight-chained, branched, cyclic andis exemplified by alkyl having one to carbon atoms such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl,cyclohexyl, octyl, decyl, etc. The aryl represented by R is exemplifiedby phenyl, a-naphthyl and B-naphthyl, etc. The substituted arylrepresented by R is exemplified by phenyl, a-naphthyl and B-naphthylwhich have one or more substituents such as lower alkyl (e.g. methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec.- butyl, tert.-butyl,etc.) and halogen (e.g. fluoro, chloro, bromo, etc.) on their rings. TheN,N-disubstituted aminomethyl represented by R is exemplified by N,N-dimethylaminomethyl, N,N-diethylaminoethyl, N,N- dipropylaminomethyl,morpholinomethyl, pyrrolidinomethyl, piperidinomethyl and substitutedpiperazinomethyl (e.g. N-methylpiperazinomethyl, N-benzylpiperazinomethyl, N-phenylpiperazinomethyl, etc.).

The new compound (I) is produced by reacting a sydnone compound of theformula (II):

\N-N R 11 L wherein R, R and are the same defined above with anacetylene compound of the formula (III):

The reaction is conducted in the presence or absence of a suitableorganic solvent such as xylene, tetralin l,2,3,4-tetrahydronaphthalene),p-cymene, chlorobenzene, mesitylene, decalin (decahydronaphthalene),etc.

The reaction is desirably conducted at an elevated temperature of notlower than C, more desirably conducted at about l50270 C. When thesolvent is xylene, for instance, the reaction proceeds so slow that afew days are required even under reflux conditions. In contrast, whentetralin is used and the reaction mixture is heated at about 200C, thereaction completes in several hours.

The proportion of the starting materials employed in the reaction may befreely employed because both the unreacted starting sydnone compound(II) and acetylene compound (III) may be easily removed from theresulting mixture. Usually, however, the starting materials aredesirably reacted either in equimolar proportions or in the presence ofan excess of acetylene compound.

Incidentally, when an asymmetrical acetylene compound is employed, thereare concurrently formed two position isomers of the resulting pyrazole.These two isomers have radicals exchanged from each other at 3- and4-positions of pyrazole ring. In any way, both isomers show effectivebiological activity.

Both position isomers are independently separable from the reactionmixture by means of per se known separating method suchasrecrystallization and column chromatography. Column-chromatography onsilica gel or alumina with benzene, chloroform, ethylacetate or amixture thereof as a developing solvent is successfully employed.

When R stands for a hydrogen atom or lower alkyl, the resulting pyrazolecompound is weakly basic. For instance, ifl-dimethylamino-3-phenylpyrazole is dissolved in ether and dry-hydrogenchloride gas is bubbled into the solution, crystals of themonohydrochloride is obtained. This compound is rather unstable and,upon addition of water, is reconverted to the free base.

On the other hand, where R is N,N-disubstituted aminomethyl group, theresulting pyrazol compound is strongly basic and, when treated with amineral acid such'as hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid and phosphoric acid, etc. or an organic acid such aspicric acid, toluenesulfonic acid, tartaric acid, oxalic acid, maleicacid, succinic acid and citric acid, etc., give a stable mono-acid salt.

The product of this invention has an effective analgesic, mild musclerelaxing and antipyretic activity and is generally administered orallyin a form of tablet, powder, capsule, etc., or by way of injection.

A typical effective dose of the product of this invention, whenadministered orally to human adult, is usually about 0.05 g. to 2.0 g. aday, desirably 0.3 g. to 1.0 g. a day and when administeredintravenously, is usually about 0.025 g. to 1.0 g. per dose. Of course,an increased or reduced dose is also effective on symptoms.

The physiological activity of the compounds of this invention isdemonstrated in the following tests.

Test for acute toxicity Each compound suspended with 4 percent gumacasia in physiological saline was administered intraperitoneally togroups each consisting of 3 mice (IRC-JCL strain, each weighing 18: 2g).Thus administered mice were observed for 8 days to calculate LD Theresults are shown in Table 1.

Test for analgesic activity Each compound suspended with 4% gurn acasiain water was administered orally to groups each consisting of 10 mice(IRC-JCL strain, each weighing 18flg.) by use of a stomach tube, andanalgesic activity was estimated according to Phenylquinone writhingsyndrome method"(cf. E.A. Siegmund et a1 J. Phar- It is to be understoodthat the following examples are solely for the purpose of illustrationand not to be construed as limitations of this invention, and that minorvariations may be resorted to without departing from the spirit andscope of this invention. Throughout the specification, kg, g, mg, ml.and mm stand for kilogram(s) gram(s), milligram(s), mil1iliter( s) andmillimeter respectively.

EXAMPLE 1 To 100 ml. of tetralin are added 12.9 g. of 3-dimethylaminosydnone and 20.4 g. of phenylacetylene, and the mixture isrefluxed at 2l0-220 C for 8 hours. Then, the excess of phenylacetyleneand tetralin are removed from the reaction mixture by distillation underreduced pressure and the residue is fractionated under reduced pressure,whereby an oily product of 1- dimethylamino-3-phenylpyrazole boiling at11l-1 C/4.5 mm Hg. is obtained. After being left standing over night theproduct crystallizes. m.p. 35-36 C Analysis C I-1 M,

C(%) H(%) Calculated 70.56 7.00 22.44 Found 70.79 6.90 22.38

The following compounds are synthesized by the same manner as above.

l-Dimethylamino-3-(p-tolyl)pyrazo1e, b.p. l34-137 C/ 5.5 mm Hg.

1-Dimethylamino-3-(p-ch1orophenyl)pyrazole, b.p.

-1l6 C/0.65 mm Hg. m.p. 45-48C.

EXAMPLE 2 To 60 ml. of tetralin are added 3.8g. of 3- morpholinosydnoneand 4.6g. of phenylacetylene and the mixture is refluxed at about 240Cfor 9 hours. The tetralin and excess of phenylacetylene are removed byvacuum distillation, and the residue is column-chromatographed on acolumn of 400 g. of silica gel, using a mixture of ethylacetate andbenzene (1:20) as a developing solvent.

The objective fractions are collected, and the solvent is removed underreduced pressure to leave crude crystals, which are allowed torecrystallize from n-hexane, whereby crystals ofl-morpholino-3-phenylpyrazole melting at 94-95C are obtained.

Analysis C H N O Calculated 68.10 6.59 18.33

Found 68.46 6.63 18.64

EXAMPLE 3 To ml. of tetralin are added 13.7 g. of 3-dimethylamino-4-morpholinomethylsydnone and 7.4 g. of phenylacetylene,and the mixture is refluxed at 205-2l0 C for 8 hours, wherebyl-dimethylamino-3- phenyl-S-morpholinomethyl-pyrazole and its positionisomer l-dimethylamino-4-phenyl-S- morpholinomethylpyrazole are producedin the reaction mixture. After the tetralin and the excess ofphenylacetylene are removed by the distillation in vacuo, the residue iscolumn-chromatographed on 400g. silica gel with 4 liters of a mixture ofethyl acetate and chloroform (1:1) using as a developing solvent toseparate the isomers from each other. Objective fractions are detectedby Dragendorff reagent and ultraviolet absorption. First, the 4-phenylcompound and then the 3-pher1yl compound is eluted from the column.After the solvent is distilled off from the latter fraction, the residueis recrystallized from 50 percent ethanol, wherebyl-dimethylamino-3-phenyl-5- morpholinomethylpyrazole melting at 81-84 Cis obtained. The chemical structure of the product is confirmed by thenuclear magnetic resonance spectrum.

Analysis C H bhO C(%) H(%) N( Calculated 67.1 1 7.74 19.56 Found 66.917.65 19.49

4.0g. of the above product is treated with methanolic solution ofhydrogen chloride and the resulting hydrochloride is recrystallized fromml. of benzene, whereupon colorless crystals ofldimethylamino-3-phenyl-5-morpholinomethylpyrazole monohydrochlon'demelting at -178C (with decomposition) are obtained.

Analysis C H N OC1 C(%) H(%) Calculated 59.53 7.18 17.36 Found 59.317.01 17.09

As the solvent is removed by distillation from the former fraction andthe residue is recrystallized from nhexane, 1 -dimethylamino-4-phenyl-5-morpholinomethylpyrazole melting at 82-84 C is obtained. The chemicalstructure of the product is confirmed by the nuclear magnetic resonancespectrum.

Analysis C l-l N O C( H(%) N(%) Calculated 67.1 1 7.74 19.56 Found 67. I7 7.58 19.62

Monohydrochloride of the above compound is obtained by the same manneras above. m.p.l93-l96 (with decomposition).

Analysis C H N OCI C(%) H( Calculated 59.53 7. 1 8 17.36 Found 59.347.17 17.39

The following compounds are obtained after the manner as above.

l-dimethylamino-3-( p-chlor ophenyl )-5 morpholinomethylpyrazolemonohydrochloride m.p. 224226 C(with decomposition)l-dimethylamino-4-(p-chlorophenyl )-5- morpholinomethylpyrazole m.p. ll9-120 C 1-dimethylamino-3 -phenyl-5-dimethylaminomethylpyrazolemonohydrochloride m.p.2ll-2l3 C (with decomposition) EXAMPLE 4dimethylamino-3,4-diphenyl-5-morpholin0methylpyrazole having melting at1 l8-l C are obtained.

Analysis C22H26N4O N( Calculated 72.90 7.23 15.46 Found 73.03 7.17 15.69

The above product is treated with methanolic solution of hydrogenchloride and the resulting hydrochloride is recrystallized from amixture of 150 ml. of acetone and 100 m1. of ether, whereupon color lesscrystals of l-dimethylamino-3,4-diphenyl-5- morpholinomethylpyrazolemonohydrochloride melting at 218-220C (with decomposition) are obtained.

Analysis C H N OCI (C%) H( N(%) Calculated 66.22 6.82 l4.04 Found 66.266.88 [4.07

EXAMPLE 5 4.3 g. of 3-dimethylamir1o-4-methylsydnone and 5.4 g. ofdiphenylacetylene are added to 60 ml. of tetralin and the mixture isrefluxed at 230-240 C for 8 hours. The tetralin is removed from thereaction mixture by distillation in vacuo and the residue is purified bycolumn-chromatography on silica gel with benzene as a developingsolvent. The solvent is distilled off from an objective fraction and theresidue is recrystallized from 60 ml. of n-hexane, whereby colorlesscrystals of 1- dimethylamino-3,4-diphenyl-5-methylpyrazole melting at 12l-l23 C are obtained.

Analysis C l-l N C(%) H(%) Calculated 77.94 6.91 15.15 Found 77.65 6.9015.03

EXAMPLE 6 Analysis C H N Calculated 77.53 6.51 15.95

Found 7737 6.56 15.55

EXAMPLE 7 To 20 ml. of tetralin are added 1.0 g. of 3- morpholinosydnoneand 1.0 grof diphenylacetylene and the mixture is refluxed at 220240 Cfor 8 hours. Then tetralin is removed from the reaction mixture bydistillation under reduced pressure, the residue is purified by columnchromatography on silica gel with a mixture of benzene and ethylacetate(20:1) used as a developer. The solvent is distilled off from anobjective fraction, whereupon pale brown crystals of 1-morpholino-3,4-diphenylpyrazole are obtained. my. l07 109 C. l 7

Analysis C H N O C(%) 11 N(%) Calculated 74.73 6.27 I3 .76 Found 75.026.34 13.81

The following compound is obtained by the same manner as above.

l-piperidino-3,4-diphenylpyrazole, m.p. 961 0 1 C.

EXAMPLE 8 To 100 ml. of tetralin are added 8.2 g. of 3-dimethylamino-4-methylsydnone and 9.5 g. of pchlorophenylacetylene andthe mixture is refluxedat 230-250 C for 8 hours. Then tetralin isremoved from the reaction mixture by distillation under reducedpressure, the residue is column chromatographed on 400 g. of silica gelwith 4 liters of benzene as a developer to separate position isomerseach other. First, the 3-pchlorophenyl compound, and then, the4-pchlorophenyl compound is eluted from the column. The crude crystalsobtained from the former fraction are recrystallized from n-hexane toobtain-1- dimethylamino-3-(p-chlorophenyl)-5-methylpyrazole as colorlesscrystals. m.p.83-85 C.

The chemical structure of the product is confirmed by the nuclearmagnetic resonance spectrum.

Analysis c l-l N Cl c l-l(%) N(%) Calculated 61.14 5.99 17.83 Found61.07 5.97 18.05

The crude crystals obtained from the latter fraction are recrystallizedfrom n-hexane, and the crystals ofldimethylamino-4-(p-chlorophenyl)-5-methylpyrazole melting at 8485 C areobtained.

The chemical structure of the product is confirmed by the nuclearmagnetic resonance spectrum.

Analysis C H N CI C(%) H( Calculated 61.14 5.99 17.83 Found 61.13 6.0318.14

EXAMPLE 9 To 120 ml. of tetralin are added 9.9 g. of3-dimethylaminosydnone and 8.9 g. of l-phenyl-l-propyne and the mixtureis refluxed at 220240 C for 8 hours. Tetralin is removed from thereaction mixture by distillation under reduced pressure and the residueis column chromatographed on 900 g. of silica gel with 9 liters of amixture of benzene and ethylacetate (:1) as a developing solvent toseparate position isomers each other. First, the 3-phenyl-4-methylcompound, and then, the 4-phenyl-3-methyl compound is eluted from thecolumn. After removing the solvent from the former fraction, the residueis fractionated under reduced pressure, wherebyl-dimethyl-amino-3-phenyl-4-methylpyrazole boiling at 137C/6 mm Hg. isobtained.

The chemical structure of the product is confirmed by the nuclearmagnetic resonance spectrum.

Analysis C H N v C(%) Calculated 71.61 7.51 20.88 Found 71.67 7.54 20.35

From the latter fraction, l-dimethylamino 3-methyl- 4-phenylpyrazoleboiling at l24-125C/3mm Hg. is obtained. The chemical structure of theproduct is confirmed by the nuclear magnetic resonance spectrum.

Analysis c H N C(%) H(%) Calculated 71.61 7.51 20.88 Found 71.98 7.6120.55

The following compounds are obtained by the same manner as above.

l-dimethylamino-4,5-dimethyl-3-phenylpyrazole. b.p. 133 C/2.7 mm Hg.

1-dimethylarnino-3 ,5-dimethyl-4-phenylpyrazole b.p. 136 C/2.5 mm Hg.,m.p. 4347 C.

EXAMPLE 10 yl)pyrazole melting at -89 C is obtained. The chemicalstructure of the product is confirmed by the nuclear magnetic resonancespectrum.

Analysis C H N Cl C(%) H(%) N(%) Calculated 64.23 6.16 16.05 Found 64.336.17 16.17

The solvent is removed from the latter fractions, whereupon crystals ofl-piperidino-4-(p-chlorophenyl)-pyrazole melting at l08-1 12 C areobtained. The chemical structure of the product is confirmed by thenuclear magnetic resonance spectrum.

Analysis C H N CI Calculalcd 64.23 6.16 16.05

Found 64.56 6.18 15.78

EXAMPLE 11 To 20 ml. of tetralin are added 2.3 g. of 3-dimethylamino-4-morpholinomethylsydnone and 1.2 g. of l-phenyl-l-propyneand the mixture is refluxed at 220-250 C for 15 hours. After cooling,the reaction mixture is poured into a large quantity of ether andextracted with a diluted hydrochloric acid. The extracted solution isneutralized with sodium bicarbonate and extracted with ether. Afterbeing washed with water, ether is distilled off and the residue ispurified by column-chromatography on g. of silica gel using 200 ml. ofethylacetate as developing solvent. Objective fractions are collectedand the solvent is distilled off. The residue is treated with methanolicsolution of hydrogen chloride and the resulting monohydrochloride isrecrystallized from acetone, whereby colorless crystals of1-dimethylamino-3- methyl-4-pheny1-5-morpholinomethylpyrazolemonohydrochloride are obtained. m.p.204-212 C (with decomposition) Thechemical structure of the product is confirmed by the nuclear magneticresonance spectrum.

Analysis C H N OCI Calculated 60.61 7.48 16.63

Found 60.38 7.51 16.63

EXAMPLE 12 To 50 ml. of tetralin are added 10 g. of 3-dimethylaminosydnone and 5.5g. of l-octyne, and the mixture is refluxed at200-2l0 C for 10 hours. After tetralin is removed by vacuumdistillation,.the residue is columnchromatographed on a column of 400 g.of silica gel, using benzene as a developing solvent. The objectivefractions are collected and the solvent is removed by distillation. Theresidue is fractionated by vacuum distillation, whereby a fraction ofl-dimethylamino-3- (n-hexyl)pyrazole boiling at 8485 C/2 mm Hg. isobtained.

Analysis C H N Calculated 67.64 10.84 21.52

Found 67.58 10.80 21.31

What is claimed is l. A l-(disubstituted-amino)pyrazole compound of theformula:

wherein each of R and R stands for lower alkyl or R and R taken togetherwith the adjacent N-atom form morpholino, piperidino, pyrrolidino,N-methylpiperazino, N-benzylpiperazino and N-phenylpiperazino, Rs, whichare the same or different from each other, stand for hydrogen, alkyl ofone to ten carbon atoms, phenyl, naphthyl, phenyl or naphthylsubstituted by halogen or lower alkyl, respectively, and R stands forhydrogen, lower alkyl, N,N-di-loweralkylaminomethyl, N-morpholinomethyl,N- piperidinomethyl, N-pyrrolidinomethyl, N-methylpiperazinomethyl,N-benzylpiperazinomethyl and N- phenylpiperazinomethyl.

2. A compound as claimed in claim 1, wherein theldi-substituted(-amino)pyrazole compound is in the form of apharmaceutically acceptable acid salt.

3. A compound as claimed in claim 2, wherein the salt is hydrochloride.

4. A compound as claimed in claim 1, wherein both R and R are methyl.

5. A compound as claimed in claim 1, wherein said compound isl-dimethylamino-3-phenylpyrazole.

6. A compound as claimed in claim 1, wherein said compound is vl-dimethylamino-3-phenyl-4-methylpyrazole.

7. A compound as claimed in claim 1, wherein said compound isl-dimethylamino-4-(p-chlorophenyl)-5-methylpyrazole.

8. A compound as claimed in claim 1, wherein said compound isl-dimethylamino-3-(p-tolyl)pyrazole.

9. A compound as claimed in claim 1, wherein said compound isl-dimethylamino-3-(p-chlorophenyl)pyrazole.

10. A compound as claimed in claim 1, wherein said compound isl-dimethylamino-3-(p-chlorophenyl)-5-rnethy1- pyrazole.

2. A compound as claimed in claim 1, wherein the1-di-substituted(-amino)pyrazole compound is in the form of apharmaceutically acceptable acid salt.
 3. A compound as claimed in claim2, wherein the salt is hydrochloride.
 4. A compound as claimed in claim1, wherein both R1 and R2 are methyl.
 5. A compound as claimed in claim1, wherein said compound is 1-dimethylamino-3-phenylpyrazole.
 6. Acompound as claimed in claim 1, wherein said compound is1-dimethylamino-3-phenyl-4-methylpyrazole.
 7. A compound as claimed inclaim 1, wherein said compound is1-dimethylamino-4-(p-chlorophenyl)-5-methylpyrazole.
 8. A compound asclaimed in claim 1, wherein said compound is1-dimethylamino-3-(p-tolyl)pyrazole.
 9. A compound as claimed in claim1, wherein said compound is 1-dimethylamino-3-(p-chlorophenyl)pyrazole.10. A compound as claimed in claim 1, wherein said compound is1-dimethylamino-3-(p-chlorophenyl)-5-methylpyrazole.